1. Field of the Invention
This invention relates to 6-amino and 6-(N-protected amino)-2,2-dimethyl-3-cyanopenams, to intermediates therefor, and to the use of the 3-cyanopenams as reactants for the preparation of 6-amino-2,2-dimethyl- 3(5-tetrazolyl)penams by reaction with a source of azide ion. More particularly, this invention relates to 6-amino- and 6-(N-protected amino)-2,2-dimethyl-3-carbamylpenams, to their use as intermediates for the preparation of corresponding 6-amino- and 6-(N-protected amino)-2,2-dimethyl-3-cyanopenams which, in turn, are converted, by reaction with a source of azide ion, to 6-amino - and 6-(N-protected amino)-2,2-dimethyl-3-(5-tetrazolyl)penams. The latter compounds are valuable intermediates for the preparation of antibacterial agents.
2. Description of the Prior Art
The penicillins a .beta.-lactam class of antibiotics, consist of N-acyl derivatives of 6-amino-2,2-dimethylpenam-3-carboxylic acid. Since the physicochemical and biological properties of the penicillins are largely determined by the nature of the C.6 substituent, chemical modification of the substituents on the penam nucleus has focused on the C.6 position.
Efforts to improve the therapeutic value of the penicillins have also led to chemical modification at the C.3 position. The 3-carboxy group has been converted to a number of other groups such as salts, anhydrides, carbamyl, esters, thioacid, hydroxymethyl, acid azide, isocyanate, carbamates, hydroxamic and nitrile [Khokhlov, et al., Doklady Akad, Sci. Nauk. S.S.S.R. 135, 875-8 (1960); C. A. 55, 11394F (1961)]. A summary of such modifications presented by HamiltonMiller, Chemotherapia, 12, 73-88 (1967).
In addition, the 3-carboxy group has been replaced by formyl [Gottstein et al., J. Org. Chem. 31, 1922 (1966)], acid chloride [Wolfe et al., Can. J. Chem. 46, 2549 (1968)], hydroxy [Heusler, Helv. Chim. Acta, 55, 388 (1972); Sheenan and Brandt, J. Amer. Chem. Soc. 87, 5468 (1965)], diazoketone [Kleiver, Khim. Geterotsikl. Soed. 1966, 702; Ramsey and Stoodley, J. Chem. Soc. (C) 1969, 1319], carboxymethyl [Kleiver loc. cit.], chloroketones (3--COCH.sub.2 Cl) [Ramsey and Stoodley, Chem. Commun. 1970, 1517], and the N-sulfonylamides (3-CONHSO.sub.2 Me) [U.S. Pat. No. 3,641,000]. With trivial exceptions of salts, certain easily hydrolyzed esters, and thioacids, all of these changes result in greatly diminished antibacterial activity.
Conversion of the 3-carboxy group of 6-amino- or 6-(N-protected amino)-2,2-dimethylpenam-3-carboxylic acids to a 5-tetrazolyl group has been found to produce penam derivatives of great value as intermediates for antibacterial agents. The compounds have the formula (I): ##STR1## wherein R is selected from the group consisting of hydrogen and amino-protecting group.
The term "amino-protecting group" as used herein is intended to include any group which will permit synthesis of compounds of formula I under the conditions, e.g. of acidity and temperature, of this process and which can be removed under conditions wherein the .beta.-lactam ring remains substantially intact. The nature of the amino-protecting group is not critical to this invention. The R group is not involved in formation of the tetrazolyl moiety. Its function is to protect the amino group and the penam ring system of 6-amino-2,2-dimethyl-3-cyanopenam during the process described in detail below for formation of compounds of formula I. It is subsequently removed at an appropriate point, generally at the ultimate or penultimate step, of the process of this invention at which point its protective function is no longer needed. The selection and identification of individual protecting groups is readily accomplished by one skilled in the art. The suitability and effectiveness of a group as an aminoprotecting group in this invention is simply determined by subjecting the 6-(N-protected-amino)-2,2-dimethyl-3-cyanopenam wherein the protecting group is the group in question to the process of the instant invention. All such groups are to be considered within the scope of this invention.
In general, all groups known, or obvious, in the art as amino-protecting groups in peptide syntheses are operative in the process of this invention. Particular interest resides in the protecting groups enumerated below because of their effectiveness in protecting the 6-amino group and their ease of removal under conditions wherein the .beta.-lactam ring remains substantially intact namely, 2,2,2-trihaloethoxycarbonyl, (e.g. 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl) and triphenylmethyl (trityl) groups, especially those of formula II below ##STR2## wherein R.sub.1, R.sub.2, and R.sub.3 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, and phenyl.
When R of formula I is hydrogen, the amino group becomes under the acid conditions of this process, an ammonium ion, and is thus protected.
Additionally, in a broad sense "amino-protecting group" as used herein also embraces acyl moieties of organic carboxylic acids. Special preference is given to 2-phenylacetyl- and 2-phenoxyacetyl groups since these are the acyl groups of penicillin G and penicillin V which serve as convenient precursors to compounds of formula I (see Reaction Scheme I below) wherein R is hydrogen.
The preferred 6-(N-protected amino)-2,2-dimethyl-3-cyanopenams for use in the process of this invention are those wherein R is a triphenylmethyl group (formula II) since such compounds are readily obtained by tritylation of 6-amino-2,2-dimethyl-3-cyanopenam or 6-APA with the appropriate halo derivative of formula II, e.g., triphenylmethyl chloride or bromide. Special preference resides in the triphenylmethyl group as amino-protecting group because of its availability.
The compounds of formula I are valuable intermediates for the synthesis of 6-acylamido-2,2-dimethyl-3-(5-tetrazolyl)penams, an effective class of antibacterial agents, by methods described herein.
For the sake of convenience, the compounds described herein are identified as derivatives of penam. The term "penam" has been defined in the J. Am. Chem. Soc., 75, 3293 (1953), as referring to the structure: ##STR3## Using this terminology, the well-known antibiotic penicillin G is designated as 6-(2-phenylacetamido)-2,2-dimethyl-penam-3-carboxylic acid. The 3-tetrazolyl surrogate of penicillin G, formula I above wherein R is 2-phenylacetyl, is designated as 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.
The 5-substituted tetrazoles as is known, can exist in two isomeric forms, viz: ##STR4## which co-exist in a dynamic tautomeric, equilibrium mixture.
A variety of methods are described in the literature for the synthesis of tetrazoles: Benson, Chem. Rev. 41, 1-61 (1947) and "Heterocyclic Compounds," Vol. 8, edited by Elderfield, John Wiley & Sons, Inc., N.Y. (1967). The preparation of 5-substituted tetrazoles by the reaction of an alkyl or aryl nitrile with hydrazoic acid is described in the above references, by Buckler et al., J. Med. Chem. 13, 725-9 (1970) and by Juby et al., J. Med. Chem. 11, 111-7 (1968). The literature methods employ rather strenuous reaction conditions such as elevated temperatures and prolonged reaction times which, if applied to the 6-amino 6-(N-protected amino)-2,2-dimethyl-3-cyanopenams of this invention, would result in considerable degradation of the reactants and products.